Automated ultra-filtration workstation

ABSTRACT

The present invention provides a disposable ultra-filtration system comprising a disposable pipetting tip and a disposable ultra-filtration cartridge, wherein the cartridge includes a membrane filtration chamber and a dead-end channel. In use, a piston in the pipette pressurizes air within the channel; the pressurized air can subsequently move the piston and cause a reverse flow back through the membrane of the cartridge, unplugging the pores thereof. Also disclosed is an automated workstation incorporating the disposable ultra-filtration system, and a system comprising the automated workstation, useful for measuring the free therapeutic drug concentration and free hormone concentration in a sample.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/725,690, filed on May 29, 2015 entitled, “Automated Ultra-filtrationApparatus”, which is a continuation of PCT Patent Application No.PCT/CA2013/050935, filed Dec. 6, 2013, claiming the benefit of U.S.Provisional Patent Application No. 61/735,041, filed Dec. 9, 2012entitled, “Disposable Ultra-filtration System”, and is herebyincorporated by reference.

FIELD OF THE INVENTION

The invention relates to a disposable ultra-filtration cartridge forpreparing an ultra-filtrate from a sample, for example serum and plasmasamples, and laboratory automation incorporating the disposableultra-filtration cartridge, whereby manual handling of samples, areminimized.

BACKGROUND OF THE INVENTION

Many medical diagnostic tests are performed in a medical laboratory, onserum and plasma. Serum is the yellow liquid obtained from whole bloodafter the blood is allowed to clot, and the clot is removed bycentrifugation; plasma is the yellow liquid obtained from blood bycentrifugation of blood mixed with an anticoagulant, e.g. heparin. Wholeblood comprises the formed elements (i.e., the cellular components andthe cell-derived components), and plasma. Red blood cells are the mostabundant formed elements in blood, and platelets are examples ofcell-derived components.

Measurement of the concentration of therapeutic drugs and certainhormones are essential in patient management, and usually, the totalconcentration of the drugs and hormones are measured because with theexception of a few hormones, e.g. thyroid hormones, the tests or assaysare designed to measure the total concentrations. Designing an assay tomeasure the concentration of the free drugs/hormones are more complex.Only the free therapeutic drugs, ions and free hormones are available tocross vascular walls and biological membranes in order to producebiological activity, by attaching to specific and non-specific bindingsites or receptors. Some examples of a therapeutic drug, an ion and ahormone are phenytoin, calcium and cortisol respectively.

Phenytoin, for example, is a therapeutic drug used to treat epilepsy. Inthe blood, about 90% of the phenytoin is bound to plasma proteins. Onlythe portion of phenytoin that is unbound or “free” is pharmacologicallyor biologically active. A test for total phenytoin represents the sum ofthe bound and unbound phenytoin. Under normal conditions, the balancebetween bound and unbound phenytoin in the blood is relatively stable,so measuring the total phenytoin is appropriate for monitoringtherapeutic levels of phenytoin. However, in certain conditions anddisease states, that balance can be upset, causing the percentage offree or active phenytoin to increase. Consequently, a patient mayexperience symptoms of phenytoin toxicity even though the totalphenytoin concentration falls within a therapeutic range. In such cases,doctors may order serum or plasma free phenytoin in order to morereliably monitor the patient's phenytoin levels, instead of serum orplasma total phenytoin.

One method used to measure free phenytoin in a patient's serum or plasmasample involves: 1) adding the patient's sample to the sample reservoirof an ultra-filtration device; 2) capping the sample reservoir; 3)placing the ultra-filtration device in a centrifuge and centrifuging forabout 25 minutes; and 4) measuring total phenytoin in the ultra-filtrateof the serum or plasma.

By way of examples only, some embodiments of a filtration apparatus thatcan be used to extract plasma from whole blood can be found in U.S. Pat.Nos. 7,816,124 and 7,807,450 awarded to the inventor. Subsequently, theinventor filed U.S. patent application Ser. No. 13/549,443 entitled“Sample Filtration Apparatus”, which describe other embodiments offiltration assemblies.

In the case of a serum or plasma sample, the filtrate (or moreappropriately, referred to as an ultra-filtrate since plasma is alreadyconsidered to be a filtrate of whole blood) usually refers to the serumor plasma containing the smaller molecular weight substances like thefree phenytoin, and the retentate usually refers to serum or plasmacontaining the higher molecular weight substances like the proteins thatbind phenytoin. An example of such a protein is albumin, having amolecular weight of about 66 kilodaltons. In contrast, the molecularweight of phenytoin is about 0.25 kilodaltons. A person of ordinaryskill in the art will appreciate that an ultra-filtrate is still afiltrate, and the term ultra-filtrate is used for clarity when thefiltrate contains substances having low molecular weights relative tothe molecular weight of large dissolved substances, for example largeproteins like immunoglobulins. Also, it seems appropriate to call thefraction of plasma having the smaller molecular weight substances aplasma ultra-filtrate, since the starting sample is plasma, which isalready considered to be a filtrate of blood.

U.S. patent application Ser. No. 13/549,443 filed by the inventordescribes cartridges for extracting plasma and serum ultra-filtrate, butthe devices can only be operated manually. Moreover, some embodiments ofthese devices require at least one manually operable compressionchamber. Moreover, in operation the sample ultra-filtration chamber isnot vented to the atmosphere. There is a need for an ultra-filtrationcartridge that can be used in an automated laboratory system, wherecentrifugation is not required and manual handling of samples areminimal.

Laboratory automation is a strategy to develop, optimize and capitalizeon technologies in the laboratory that enable new and improved processesfor reducing laboratory process times. The most widely known applicationof laboratory automation technology is laboratory robotics. Moregenerally, the field of laboratory automation comprises many differentautomated laboratory analyzers, devices, software algorithms, andmethodologies used to enable, expedite and increase the efficiency andeffectiveness of providing test results.

The automated process of providing plasma and serum ultra-filtrates, forexample, can be incorporated in laboratory automation, and the plasmaand serum ultra-filtrates used to measure therapeutic drugs, ions andhormones, for example.

SUMMARY OF THE INVENTION

The present invention provides a disposable ultra-filtration system forautomatic preparation of an ultra-filtrate from a sample, the systemcomprising a disposable ultra-filtration cartridge and a disposablepipetting tip. The disposable ultra-filtration cartridge includes: a) atop end having at least one opening providing an ultra-filtrate chambervent and an ultra-filtrate chamber opening; b) a bottom end forsupporting the disposable ultra-filtration cartridge in an uprightposition in cooperation with a cartridge rack; c) a filtration chambercomprising (i) a membrane having a retentate side, a filtrate side, anda predetermined pore size, (ii) a sample inlet for sealably engaging thedisposable pipetting tip containing the sample, (iii) a retentateoutlet, (iv) an ultra-filtrate chamber defined substantially by thefiltrate side of the membrane, an ultra-filtrate chamber opening for theultra-filtrate to flow out of the ultra-filtrate chamber and the spacetherebetween, and (v) an ultra-filtrate chamber vent for enabling theultra-filtrate to flow out of the ultra-filtrate chamber opening; d) adead-end channel having an open end and a sealed end, wherein the openend is coincident with the retentate outlet; e) an ultra-filtratereservoir at the bottom end for collecting the ultra-filtrate. Thedisposable pipetting tip includes a piston movable in one direction byapplying a force to pressurize trapped air in the dead-end channel. Whenthe force is relaxed the piston is movable in the opposite direction bythe pressurized trapped air in the dead-end channel to accommodatereverse flow of retentate to unplug the pores.

The present invention also provides an automated workstation forpreparing ultra-filtrate in a disposable ultra-filtration system, theautomated workstation operating in cooperation with a controller andcomprising: a) a base; b) one or more cartridge racks for holding theone or more disposable ultra-filtration cartridges of the disposableultra-filtration system, and cartridge rack positions on the base forpositioning the one or more cartridge racks in predetermined locations;c) cartridge rack detectors for detecting the presence of a cartridgerack on the base at the predetermined locations, the cartridge rackdetectors having an output element for signaling the presence of thecartridge rack to the controller; d) one or more sample tube racks forholding one or more sample tubes, and sample tube rack positions on thebase for positioning the sample tube racks in predetermined locations;e) sample tube rack detectors for detecting the presence of a sampletube rack on the base at the predetermined locations, the sample tuberack detectors having an output element for signaling the presence ofthe sample tube rack to the controller; f) one or more pipetting tipracks for holding one or more disposable pipetting tips of thedisposable ultra-filtration system, and pipetting tip rack positions onthe base for positioning the pipetting tip racks in predeterminedlocations; g) pipetting tip rack detectors for detecting the presence ofa pipetting tip rack on the base at the predetermined locations, thepipetting tip rack detectors having an output element for signaling thepresence of the pipetting tip rack to the controller; h) a pipettingtool for releasably engaging the one or more disposable pipetting tips;i) a movable arm, supported from the base, for supporting the pipettingtool; and j) a waste container for receiving released disposablepipetting tips. The pipetting tool is configured to apply a force tomove a piston of the one or more disposable pipetting tips to pressurizetrapped air in a dead-end channel of the one or more disposableultra-filtration cartridges.

The present invention also provides a system for measuring at least oneof a free therapeutic drug concentration and a free hormoneconcentration in one or more samples, the samples being one of serum andplasma, the system comprising: a) an analyzer calibrated to measure atleast one of a total therapeutic drug concentration and a total hormoneconcentration; b) a controller comprising memory storage and a datainput element for inputting processing instructions for the one or moresamples, the processing instructions being stored in the memory storage;c) an automated workstation operating in cooperation with thecontroller, the automated workstation being capable of preparing one ormore ultra-filtrates in one or more disposable ultra-filtrationcartridges of a disposable ultra-filtration system, the automatedworkstation having a transport system for accepting the one or moresamples and releasing the one or more ultra-filtrates in reservoirs ofthe one or more ultra-filtration cartridges, the automated workstationalso having a pipetting tool for releasably engaging one or moredisposable pipetting tips of the disposable ultra-filtration system; andd) a track for transporting the one or more ultra-filtrates from theautomated workstation to the analyzer. The analyzer is used to measureat least one of a free therapeutic drug concentration and a free hormoneconcentration in the one or more ultra-filtrates prepared by theautomated workstation. The pipetting tool is configured to apply a forceto move a piston of the one or more disposable pipetting tips topressurize trapped air in a dead-end channel of the one or moredisposable ultra-filtration cartridges.

Some embodiments of the system further comprise an indicia reader fortracking the one or more sample tubes and the one or more disposableultra-filtration cartridges. The indicia comprises one of aone-dimensional barcode, a two-dimensional barcode, and a radiofrequency identification tag attached to the one or more sample tubesand the one or more disposable ultra-filtration cartridges.

Other aspects and features of the present invention will becomeapparent, to those ordinarily skilled in the art, upon review of thefollowing description of the specific embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention, and to show moreclearly how it may be carried into effect, reference will now be made,by way of example, to the accompanying drawings, which illustrateaspects of embodiments of the present invention and in which:

FIG. 1A is a schematic drawing showing details of a top view of anultra-filtration cartridge 20 used for preparing an ultra-filtrateaccording to a first embodiment of the ultra-filtration cartridge;

FIG. 1B is a right side view of the cartridge 20 shown in FIG. 1A;

FIG. 1C is a first cross-sectional view through the cartridge 20 shownin FIG. 1B along line C-C;

FIG. 1D is a front view of the cartridge 20 shown in FIG. 1A;

FIG. 1E is a second cross-sectional view through the cartridge 20 shownin FIG. 1D along line E-E;

FIG. 1F is a third cross-sectional view through the cartridge 20 shownin FIG. 1D along line F-F;

FIG. 1G is a perspective view of the apparatus 20 shown in FIG. 1A;

FIG. 2A is schematic drawing showing details of a top view of a hollowfiber filtration membrane assembly 60 a shown in FIGS. 10 and 1F;

FIG. 2B is a right side view of the hollow fiber filtration membraneassembly 60 a shown in FIGS. 10 and 1F;

FIG. 2C is a front view of hollow fiber filtration membrane assembly 60a shown in FIG. 2A;

FIG. 2D is a perspective view of the hollow fiber filtration membraneassembly 60 a shown in FIG. 2A

FIG. 2E is a cross-sectional view through the hollow fiber filtrationmembrane assembly 60 a shown in FIG. 2C along line E-E;

FIG. 2F is a detailed view of detail F shown in FIG. 2E showing aschematic representation of the membrane 67 a;

FIG. 3A is a schematic drawing showing details of a top view of anassembly comprising an ultra-filtration cartridge 40 according to asecond embodiment of the ultra-filtration cartridge, sealably engagedwith a pipetting tip 70, used for preparing an ultra-filtrate;

FIG. 3B is a front view of the assembly comprising the cartridge 40 andthe pipetting tip 70 shown in FIG. 3A;

FIG. 3C is a first cross-sectional view through the assembly comprisingthe cartridge 40 and the pipetting tip 70 shown in FIG. 3B along lineC-C;

FIG. 3D is a second cross-sectional view through the assembly comprisingthe cartridge 40 and the pipetting tip 70 shown in FIG. 3B along lineD-D;

FIG. 3E is a perspective view of the pipetting piston 87 shown incross-section in FIG. 3D;

FIG. 3F is a perspective view of the pipetting tip 70 alone;

FIG. 3G is a perspective view of the upper portion 30 of the cartridge40 shown FIG. 3A, FIG. 3B and FIG. 3D;

FIG. 3H is a perspective view of the lower portion 10 of the cartridge40 shown FIG. 3A, FIG. 3B and FIG. 3D;

FIG. 4A is a schematic drawing showing details of a top view of theultra-filtration cartridge 40 used for preparing an ultra-filtrateaccording to the second embodiment of the ultra-filtration cartridge,comprising the upper section 30 shown in two parts 30′ and 30″, and thelower section 10, with section 30″ at the top;

FIG. 4B is a front view of the cartridge 40 shown in FIG. 4A;

FIG. 4C is a top view of cartridge 40 shown in FIG. 4A, with parts 30″and lower section 10 hidden;

FIG. 4D is a front view of the cartridge 40 shown in FIG. 4C;

FIG. 4E is a top view of cartridge 40 shown in FIG. 4A, with parts 30″,lower section 10 and filtration membrane assembly 60 b hidden;

FIG. 4F is a front view of the cartridge 40 shown in FIG. 4E;

FIG. 4G is a schematic drawing showing details of a top view of anultra-filtration cartridge 40 used for preparing an ultra-filtrateaccording to a second embodiment of the ultra-filtration cartridge,comprising the upper section 30 shown in two parts 30′ and 30″, and thelower section 10, with section 30′ at the top;

FIG. 4H is a front view of the cartridge 40 shown in FIG. 4G;

FIG. 4J is a top view of cartridge 40 shown in FIG. 4G, with parts 30′and lower section 10 hidden;

FIG. 4K is a front view of the cartridge 40 shown in FIG. 4J;

FIG. 4L is a top view of cartridge 40 shown in FIG. 4G, with parts 30′,lower section 10 and filtration membrane assembly 60 b hidden;

FIG. 4M is a front view of the cartridge 40 shown in FIG. 4L;

FIG. 5A is a schematic drawing showing details of a front view of thefiltration membrane assembly 60 b shown in FIG. 4D and FIG. 4K;

FIG. 5B is a top view of the filtration membrane assembly 60 b shown inFIG. 5A;

FIG. 5C is a bottom view of the filtration membrane assembly 60 b shownin FIG. 5A;

FIG. 5D is a first perspective view of the filtration membrane assembly60 b shown in FIG. 5A;

FIG. 5E is a second perspective view of the filtration membrane assembly60 b shown in FIG. 5A;

FIG. 5F is a third perspective view of the filtration membrane assembly60 b shown in FIG. 5A;

FIG. 5G is a fourth perspective view of the filtration membrane assembly60 b shown in FIG. 5A;

FIG. 5H is a cross-sectional view of the filtration membrane assembly 60b shown in FIG. 5A along line H-H;

FIG. 5J is a detailed view of detail J shown in FIG. 5H showing aschematic representation of the membrane 67 b;

FIG. 6A is a schematic drawing showing details of a top view of anassembly comprising an ultra-filtration cartridge 50 according to athird embodiment of the ultra-filtration cartridge, engaged with apipetting tip 70, used for preparing an ultra-filtrate;

FIG. 6B is a right side view of the assembly comprising the cartridge 50and the pipetting tip 70 shown in FIG. 6A;

FIG. 6C is a first cross-sectional view through the assembly comprisingthe cartridge 50 and the pipetting tip 70 shown in FIG. 6B along lineC-C;

FIG. 6D is a perspective view of the cartridge 50 shown FIG. 6B and FIG.6F;

FIG. 6E is a perspective view of the pipetting tip 70 shown FIG. 6B andFIG. 6F;

FIG. 6F is a front view of the assembly comprising the cartridge 50 andthe pipetting tip 70 shown in FIG. 6A;

FIG. 6G is a second cross-sectional view through the assembly comprisingthe cartridge 50 and the pipetting tip 70 shown in FIG. 6F along lineG-G;

FIG. 6H is a third cross-sectional view through the assembly comprisingthe cartridge 50 and the pipetting tip 70 shown in FIG. 6F along lineH-H;

FIG. 6J is an enlarged of the cross-sectional view shown in FIG. 6H;

FIG. 7A is a schematic drawing showing details of a top view of anultra-filtration cartridge 50 used for preparing an ultra-filtrateaccording to a third embodiment of the ultra-filtration cartridge, shownin three parts 50′, 50″ and 50′″, with the part 50′″ at the bottom;

FIG. 7B is a front view of the cartridge 50 shown in FIG. 7A;

FIG. 7C is a top view of cartridge 50 shown in FIG. 7A, with front part50′″ hidden;

FIG. 7D is a front view of the cartridge 50 shown in FIG. 7C;

FIG. 7E is a top view of cartridge 50 shown in FIG. 7A, with the frontpart 50′″ and the middle part 50″ hidden;

FIG. 7F is a front view of the cartridge 50 shown in FIG. 7E;

FIG. 7G is a top view of the cartridge 50 shown in FIG. 7A, with thefront part 50′″, the middle part 50″ and the and filtration membraneassembly 60 c hidden;

FIG. 7H is a front view of the cartridge 50 shown in FIG. 7G;

FIG. 7J is a schematic drawing showing details of a top view of anultra-filtration cartridge 50 used for preparing an ultra-filtrateaccording to a third embodiment of the ultra-filtration cartridge, shownin three parts 50′, 50″ and 50′″, with the part 50′ at the bottom;

FIG. 7K is a front view of the cartridge 50 shown in FIG. 7J;

FIG. 7L is a top view of cartridge 50 shown in FIG. 7J, with back part50′ hidden;

FIG. 7M is a front view of the cartridge 50 shown in FIG. 7L;

FIG. 7N is a top view of cartridge 50 shown in FIG. 7J, with the backpart 50′ and the filtration membrane assembly 60 c hidden;

FIG. 7P is a front view of the cartridge 50 shown in FIG. 7N;

FIG. 7R is a top view of the cartridge 50 shown in FIG. 7A, with theback part 50′, the filtration membrane assembly 60 c and the middle part50″ hidden;

FIG. 7S is a front view of the cartridge 50 shown in FIG. 7R;

FIG. 7T is a cross-sectional view through the cartridge 50 shown in FIG.7K along line T-T;

FIG. 8A is a schematic drawing showing details of a front view of thefiltration membrane assembly 60 c shown in FIG. 6F and FIG. 6M;

FIG. 8B is a top view of the filtration membrane assembly 60 c shown inFIG. 8A;

FIG. 8C is a bottom view of the filtration membrane assembly 60 c shownin FIG. 8A;

FIG. 8D is a first perspective view of the filtration membrane assembly60 c shown in FIG. 8A;

FIG. 8E is a second perspective view of the filtration membrane assembly60 c shown in FIG. 8A;

FIG. 8F is a third perspective view of the filtration membrane assembly60 c shown in FIG. 8A;

FIG. 8G is a fourth perspective view of the filtration membrane assembly60 c shown in FIG. 8A;

FIG. 8H is a cross-sectional view of the filtration membrane assembly 60c shown in FIG. 8A along line H-H;

FIG. 8J is a detailed view of detail J shown in FIG. 8H showing aschematic representation of the membrane 67 c;

FIG. 9A is a schematic drawing showing details of a top view of anotherembodiment 60 d of a filtration membrane assembly;

FIG. 9B is a back view of the filtration membrane assembly 60 d shown inFIG. 9A;

FIG. 9C is a front view of the filtration membrane assembly 60 d shownin FIG. 9A;

FIG. 9D is a right side view of the filtration membrane assembly 60 dshown in FIG. 9A;

FIG. 9E is a first perspective view of the filtration membrane assembly60 d shown in FIG. 9A;

FIG. 9F is a second perspective view of the filtration membrane assembly60 d shown in FIG. 9A;

FIG. 9G is a third perspective view of the filtration membrane assembly60 d shown in FIG. 9A;

FIG. 9H is a fourth perspective view of the filtration membrane assembly60 d shown in FIG. 9A;

FIG. 9J is a cross-sectional view of the filtration membrane assembly 60d shown in FIG. 9C along line J-J;

FIG. 9K is a detailed view of detail K shown in FIG. 9J showing aschematic representation of the membrane 67 d;

FIG. 10A is a schematic drawing showing details of a top view of anotherembodiment 60 e of a filtration membrane assembly;

FIG. 10B is a back view of the filtration membrane assembly 60 e shownin FIG. 9A;

FIG. 100 is a front view of the filtration membrane assembly 60 e shownin FIG. 10A;

FIG. 10D is a right side view of the filtration membrane assembly 60 eshown in FIG. 10A;

FIG. 10E is a first perspective view of the filtration membrane assembly60 e shown in FIG. 10A;

FIG. 10F is a second perspective view of the filtration membraneassembly 60 e shown in FIG. 10A;

FIG. 10G is a third perspective view of the filtration membrane assembly60 e shown in FIG. 10A;

FIG. 10H is a fourth perspective view of the filtration membraneassembly 60 e shown in FIG. 10A;

FIG. 10J is a first cross-sectional view of the filtration membraneassembly 60 e shown in FIG. 10B along line J-J;

FIG. 10K is a second cross-sectional view of the filtration membraneassembly 60 e shown in FIG. 100 along line K-K;

FIG. 11A is a schematic drawing showing details of a top view of aworkstation 100 for automatically preparing sample ultra-filtrate from asample;

FIG. 11B is a top view of the workstation 100 shown in FIG. 11A;

FIG. 11C is a detailed view of detail C shown in FIG. 11B showingdetails of ultra-filtration cartridges in an ultra-filtration cartridgerack, and ultra-filtration cartridge reservoir containing sampleultra-filtrate, in an analyzer sector for presenting sampleultra-filtrate to the analyzer;

FIG. 11D is a first perspective view of the workstation 100 shown inFIG. 11A;

FIG. 11E is a second perspective view of the workstation 100 shown inFIG. 11A;

FIG. 12A is a schematic drawing showing details of a top view of anultra-filtration system 800 for automatically preparing serum or plasmaultra-filtrate from a sample and presenting the ultra-filtrate to ananalyzer for measuring free therapeutic drugs and hormones in serum orplasma;

FIG. 12B is a top view of the system 800 shown in FIG. 12A;

FIG. 12C is perspective view of the system 800 shown in FIG. 12A; and

FIG. 12D is a detailed view of detail D shown in FIG. 12C showingdetails of ultra-filtration cartridges in an ultra-filtration cartridgerack, ultra-filtration cartridge reservoir containing sampleultra-filtrate, in an analyzer sector for presenting sampleultra-filtrate to the analyzer, and ultra-filtration cartridge reservoircontaining sample ultra-filtrate in an analyzer sector, on a transporttrack used to present the sample ultra-filtrate to the analyzer.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The reference numerals used in describing the preferred embodiments ofthe invention are provided in Table 1.

TABLE 1 Reference Numerals Description of Structural Features 10 A bodyof an ultra-filtration cartridge reservoir according to the secondembodiment of an ultra-filtration cartridge 20 A first embodiment of anultra-filtration cartridge 27 An opening for allowing access toultra-filtrate reservoir 30 A body comprising a filtration chamber of anultra-filtration cartridge according to the second embodiment of anultra- filtration cartridge 31 A vent fluidly connected to the filtrateside of the membrane 33 Retentate side of membrane and adjacent space 35Filtrate side of membrane and adjacent space, the adjacent space being aportion of an ultra-filtrate chamber (An ultra- filtration chamber isnot shown as a specific structure, but refers substantially to spacedefined by the filtrate side of the membrane, the ultra-filtrate chamberoutlet 39, and the space therebetween) 37 A channel fluidly connectingfiltrate side of membrane and adjacent space, with ultra-filtratechamber outlet 39 An ultra-filtrate chamber outlet 40 A secondembodiment of an ultra-filtration cartridge 41 A bottom cavity of anultra-filtrate reservoir of an ultra- filtration cartridge 43 An openingfor allowing pipetting tip to access inlet of the filtration chamber 45A cavity occupied by a pipetting tip when the pipetting tip is engagedwith ultra-filtration cartridge 47 A filtration chamber inlet forsealably engaging pipetting tip 48 An extension of the filtration inlet,fluidly connected to the filtration chamber 49 A filtration chamberoutlet, coincident with the open end of a dead-end channel 51 50 A thirdembodiment of an ultra-filtration cartridge 51 A dead-end channel of anultra-filtration cartridge 53 A sealed end of a dead-end channel 51 ofan ultra-filtration cartridge 60 A filtration membrane assembly 61 Afirst flange in membrane assembly 62 A filtration membrane assemblysupporting structure 63 A second flange in membrane assembly 65 A hollowfiber filtration membrane 67 A filtration membrane (Wall of a hollowfiber filter when the filtration membrane is in the form of a hollowfiber filter) 69 A cavity usually occupied by a filtration membraneassembly 70 A pipetting tip 73 A pipetting tip housing 77 A pipettingtip housing recess 79 A pipetting tip piston flange 81 A pipetting tiphousing gripping end 83 A pipetting tip housing piston flange stop(inclined interior wall of pipetting tip housing) 85 A pipetting tipdispensing end 87 A pipetting tip piston 89 A pipetting tip pistongripping stem 91 A pipetting tip piston flange upper face 93 A pipettingtip piston flange lower face 95 A pipetting tip piston sealing O-ring100 A workstation for automatically preparing sample ultra- filtratefrom the sample 110 Pipetting tool for releasably holding a pipettingtip 112 A pipetting tool carriage for supporting and cooperating withpipetting tool 114 A pipetting tool carriage movable arm for supportingand moving pipetting tool carriage 116 A pipetting tool carriage movablearm carriage 120 A pipetting tip rack 122 A pipetting tip 130 A grippingtool for gripping for example, a sample tube or an ultra-filtrationcartridge, to enable transportation thereof 132 A gripping tool carriagefor supporting and cooperating with gripping tool 134 A gripping toolcarriage movable arm for supporting and moving gripping tool carriage136 A gripping tool carriage movable arm 138 A track for facilitatingmovement of pipetting tool carriage movable arm carriage and grippingtool carriage movable arm 140 An ultra-filtration cartridge rack 142 Anultra-filtration cartridge (one similar to the third embodiment of anultra-filtration cartridge 50 is shown) 144 A projected member in theultra-filtration cartridge rack, for enabling proper orientation ofultra-filtration cartridge when it is located in the ultra-filtrationrack for processing a sample 150 A sample tube rack 152 A sample tube160 A waste container for receiving ejected used pipetting tip 170 Acontroller 172 A controller data input element and display touch screen180 An analyzer sector for presenting sample ultra-filtrate to theanalyzer 190 An ultra-filtration cartridge reservoir containing sampleultra- filtrate (The third embodiment of an ultra-filtration cartridgeis shown as this example, wherein the reservoir is an integral part ofthe ultra-filtration cartridge.) 200 An automated workstation base 202An automated workstation supporting frame A pipetting tip rack site forhousing pipetting tips contained in pipetting tip racks 204 A sampledelivery site on the workstation for receiving samples in sample tubescontained in sample tube racks 206 An ultra-filtration cartridge racksite for on the workstation for housing ultra-filtration cartridgescontained in ultra- filtration cartridge racks 208 An analyzer sectorsite on the workstation for housing analyzer sectors 300 An analyzer,for example, an immunoanalyzer for performing immunoassays 400 Atransport track for transporting a single ultra-filtration cartridgereservoir containing sample ultra-filtrate or a plurality ofultra-filtration cartridge reservoirs containing sample ultra-filtratesin analyzer sectors 500 A workstation table for aligning the workstationwith the analyzer on a horizontal plane 800 An ultra-filtration systemfor measuring free therapeutic drugs and free hormones in serum orplasma

The same reference numerals are used to represent similar structuralfeatures in different embodiments. In some cases, letters are added tothe end of the numerals to indicate different embodiments. For example,the indicia 60 is used to represent a filtration membrane assembly, butin the first embodiment (20), second embodiment (40), and thirdembodiment (50), the indicia 60 a, 60 b, and 60 c are used to refer tothe filtration membrane assembly in the respective embodiments.

The present invention describes several embodiments of disposableultra-filtration cartridges for automatic preparation of sampleultra-filtrates. The sample used with the present invention is one ofserum or plasma. However, the sample can be any biological sample aswell as a non-biological sample. The ultra-filtration cartridge can beused in a stand-alone automated workstation operating in cooperationwith a controller, or can be used in an automated workstation that isintegrated into an automated laboratory, operating in cooperation with amore centralized controller.

To the best knowledge of the inventor, there is no known automatedworkstation or system that includes ultra-filtration cartridges forpreparing sample ultra-filtrates automatically, without the use of acentrifuge. Moreover, there is no known automated system for measuringfree fractions (i.e., not bound to substantially larger molecules likeproteins, for example albumin) of a therapeutic drug or a hormone, usingthe assays designed to measure total drug or total hormone concentrationin plasma or serum.

Disposable ultra-filtration cartridges are described, followed by anautomated workstation, and finally a system that expands beyond theworkstation is described. Some embodiments of the ultra-filtrationcartridges are described as seamless units and some are described ascomprising parts that can be easily manufactured by for example, plasticmolding or 3-D printing; the parts are then assembled together using forexample, double-sided sticky gasket, application of glue to the faces orultrasonic welding. By illustrating some of the embodiments ofcartridges in parts, ideas are provide regarding manufacturing thecartridges, and the parts provide views of internal structures, withouthaving to view cross-sections.

An element of the disposable ultra-filtration cartridges is a filtrationmembrane assembly. Several embodiments of filtration membrane assemblyare illustrated, for example filtration membrane assemblies 60 aillustrated in FIGS. 2A-2F, 60 b illustrated in FIGS. 5A-5J, 60 cillustrated in FIGS. 8A-8J, 60 d illustrated in FIGS. 9A-9K, and 60 eillustrated in FIGS. 10A-10K. For a more general description of amembrane, the side of the membrane in contact with retentate is referredto as the retentate side, and the side of the membrane in contact withthe filtrate is referred to as the filtrate side. When the sample isplasma, the retentate will initially be plasma, which progressivelybecomes more concentrated plasma; the filtrate will be a plasmaultra-filtrate. A person of ordinary skill in the art will appreciatethat the membrane could take on any shape, provided that the membraneallows sample ultra-filtrate to travel from the retentate side to thefiltrate side, and a barrier is maintained between the retentate sideand the filtrate side. The pore size of the membrane depends on the sizeof molecules that are required to pass through the filtration membrane.

Another element of the present invention is a filtration chamber. Aperson of ordinary skill in the art will appreciate that a filtrationchamber does not point to any isolated structure in the embodiments ofthe invention, but refers to a general structure that comprises afiltration membrane assembly, a sample inlet fluidly connected to theretentate side of the membrane, and a retentate outlet for outflow ofthe fraction of sample that does not penetrate the membrane, and anoutlet for the fraction of sample that penetrates the membrane. Thespace occupied by the filtration chamber is illustrated as cavity 69 ain FIG. 1E. Flow across a surface of the membrane effectively reducessample viscosity, and unplugs the membrane pores.

Referring collectively to FIGS. 1A-1G, shown are different views of anultra-filtration cartridge 20 according to a first embodiment of anultra-filtration cartridge. Cartridge 20 represents a disposableultra-filtration cartridge for automatic preparation of sampleultra-filtrate. The cartridge has a top end shown in FIG. 1A, and abottom end for supporting the cartridge in an upright position incooperation with a cartridge rack. The cartridge can be provided inindividual holders or racks for holding more than one cartridge. Thebottom end is shown in FIG. 1D as the part towards the bottom of thepage, and in FIG. 1B as the part towards the right side of the page. Atthe top end is shown an opening 27 a for allowing access to anultra-filtrate reservoir 41 a, a vent 31 a for enabling theultra-filtrate to flow into the ultra-filtrate reservoir 41 a, and anopening 43 for allowing a pipetting tip to access sample inlet 47 a of afiltration chamber. Also shown in FIG. 1A is an ultra-filtrate chamberoutlet 39 a, shown clearly in FIG. 1C. A right side view, a top view anda perspective view of ultra-filtration cartridge 20 are shown in FIGS.1B, 1D, and 1G respectively. The bottom of the cartridge is intended tofit in a cartridge rack or analyzer sector, so that the opening 27 a tothe ultra-filtrate reservoir 41 a is substantially concentric with theannular shape of the bottom of the cartridge, in order for an analyzersampling probe to have unobstructive access to the ultra-filtrate.

A cross-sectional view of the cartridge 20 shown in FIG. 1B through lineC-C is shown as FIG. 10. Shown are a filtration membrane assembly 60 a,portion of the an ultra-filtrate chamber shown as 35 a, theultra-filtrate chamber outlet 39 a, and a vent 31 a fluidly connected tothe ultra-filtrate chamber, and a channel 37 a fluidly connectingfiltrate side of membrane and adjacent space 35 a with theultra-filtrate chamber outlet 39 a. The ultra-filtrate chamber is notshown as a specific structure, but refers substantially to space definedby the filtrate side of the membrane, the ultra-filtrate chamber outlet39 a, and the space therebetween. Also shown is a cross-sectional viewof a dead-end channel 51 a (see FIG. 1E).

Cross-sectional views of the cartridge 20 shown in FIG. 1D through linesE-E and F-F are shown as FIGS. 1E and 1F respectively. A cavity 69 a isshown in FIG. 1E, which is usually occupied by the membrane assembly 60a, and is therefore a substantial representation the space occupied bythe filtration chamber. Details of the filtration membrane assembly 60 aare shown collectively in FIGS. 2A-2F. The filtration membrane assembly60 a comprises hollow fibers 65 a, and perforated flanges 61 a and 63 a.The flanges 61 a and 63 a provide support for the individual hollowfibers 65 a, and the annular surface of the flanges provide seals whenthe assembly 60 a is installed in the cavity 69 a. The outside portionsof the fibers 65 a are also sealed at the flanges, in order to providefluid-tight separation between ultra-filtrate and retentate. Sealing canbe accomplished by, for example, a resin or glue, without obstructingthe lumens of the fibers. A cross-section of the membrane 67 a, which isthe wall of the hollow fiber, is shown as F in FIG. 2E, and details of Fis shown in FIG. 2F, showing the filtrate side 35 a, and the retentateside 33 a of the membrane 67 a. In other embodiments as illustrated inFIG. 9K for example, the filtrate side is 33 d and the retentate side is35 d.

Referring to FIG. 1E, shown is a dead-end channel 51 a having an openend 49 a and a sealed end 53 a. The open end 49 a of the dead-endchannel 51 a is coincident with the filtration chamber outlet. Alsoshown is a cavity 45 a occupied by a pipetting tip when the pipettingtip is engaged with ultra-filtration cartridge. Details of a pipettingtip 70 are shown in FIGS. 3B, 3D, and 3F, in association with a secondembodiment 40 of an ultra-filtration cartridge. In operation the sampleinlet 47 a is sealably engaged with the dispensing end 85 of adisposable pipetting tip 70 containing sample.

Referring to FIGS. 3B, 3D, 3E, and 3F, shown are details of thepipetting tip 70. The pipetting tip 70 comprises a pipetting tip housing73, a pipetting tip housing recess 77, a pipetting tip piston flange 79,a pipetting tip housing gripping end 81, a pipetting tip housing pistonflange stop (inclined interior wall of pipetting tip housing) 83, apipetting tip dispensing end 85, a pipetting tip piston 87, a pipettingtip piston gripping stem 89, a pipetting tip piston flange upper face91, a pipetting tip piston flange lower face 93, and a pipetting tippiston sealing O-ring 95 at a piston sealing end (or any other means formoving the piston 87 inside the pipetting tip housing 73 in afluid-tight manner). This type of positive displacement pipetting systemis known, for example, U.S. Pat. No. 4,474,071 teaches a manuallyoperable positive displacement pipette.

Still referring to FIGS. 3B, 3D, 3E, and 3F, the pipetting tip 70operates in cooperation with a pipetting tool 110 shown in a workstation100 illustrated in FIG. 11E. Details are not shown, but the pipettingtool 110 comprises resilient fingers that open radially by movementagainst the force exerted by a spring, whereby the resilient fingers cangrab the pipetting tip piston gripping stem 89 up to and not beyond thepipetting tip piston flange upper face 91. An outer sleeve of thepipetting tool surrounding the resilient fingers frictionally engagesthe pipetting tip recess 77, enabling the pipetting tool 110 to move thepipetting piston 87 inside the pipetting tip housing 73 in a fluid-tightmanner. By pushing the piston flange lower face 93 against the pipettingtip housing piston flange stop (inclined interior wall of pipetting tiphousing) 83, and both the pipetting tip housing 73 and the pipetting tippiston 87 can be ejected into a waste container, as directed by acontroller 170 that works in cooperating with the pipetting tool 110(see workstation 100 shown in FIGS. 11D and 11E).

Referring to FIG. 1E, the pipetting tip 70 containing sample is insertedthrough the opening 43 a into the cavity 45 a, and sealably engages thefiltration chamber inlet 47 a. Force is applied to the piston 87,simultaneously forcing sample into the filtration chamber andcompressing the air in the dead-end channel 51. After relaxing the forceon the piston 87 to a predetermined level, the compressed air in thedead-end channel 51 reverses the flow of retentate. By repeating thispiston force-release cycle, a forward and backward flow of sample acrossthe surface of the membrane 67 a is created, and trans-membrane pressureis created as well, causing ultra-filtrate to accumulate on the filtrateside of the membrane 35 a. The vent 31 a facilitates flow ofultra-filtrate into the bottom cavity of an ultra-filtrate reservoir 41a. The forward and backward flow of retentate across the membrane is ameans for continuously washing the retentate side of the membrane andunplugging the membrane pores. The amount of ultra-filtrate thataccumulates in the reservoir 41 a is proportional to the number ofpiston force-release cycles.

Referring collectively to FIGS. 3A-3H and FIGS. 4A-4M, shown is a secondembodiment of a disposable ultra-filtration cartridge 40 for automaticpreparation of sample ultra-filtrate. Cartridge 40 is similar tocartridge 20 and accordingly, elements common to both cartridges sharecommon reference numerals, but the letter “b” appended at the end ofreference numerals to indicate a different embodiment; the letter “a” isused for cartridge 20. The pipetting tip 70 was previously describedwhen cartridge 20 was described. A first difference between cartridge 40and cartridge 20 are that the filtration membrane assembly 60 b shown inFIGS. 4D and 4K are very different, and details of the filtrationmembrane assembly 60 b are shown collectively in FIGS. 5A-5J. A seconddifference is that the opening 43 b for allowing pipetting tip 70 toaccess the inlet 47 b of the filtration chamber is substantiallyconcentric with the circular shape of the cartridge along a horizontalplane. The implication is that in operation, the cartridge 40 does nothave to be in any particular orientation (with respect to the X-Z andY-Z planes) in the ultra-filtration cartridge rack 140 shown in FIG. 11Eand FIG. 12D in the workstation 100 shown collectively in FIGS. 11A-11E,which shows a cartridge 142. Cartridge 142 is very similar to cartridge20, in that the opening 43 a is offset from the central vertical axis,and therefore the cartridges 142 have to be aligned with the programmedpositions of the pipetting tool 110. In other words, opening 43 a and 27a shown in FIGS. 1A and 1G are not aligned with each other. In contrast,opening 43 b (see FIG. 3G) and opening 27 b (see FIG. 3H) aresubstantially concentric.

Still referring collectively to FIGS. 3A-3H, and FIGS. 4A-4M, a thirddifference between cartridge 20 and 40 is that cartridge 40 comprises anupper section 30 frictionally engaged with a lower section 10. The uppersection 30 comprises the filtration chamber, and the lower section isthe ultra-filtrate reservoir with bottom cavity 41 b. After processing asample, upper section 30 is automatically removed with a gripping toolas for example, a gripping tool 130 shown in the workstation 100 (seeFIGS. 11A & 11D). The remaining ultra-filtrate reservoir 10 containingultra-filtrate is presented to an analyzer, like for example, analyzer300 shown in FIGS. 12A-12C. As mentioned previously, some cartridges areshown in pieces, so that the individual pieces can be manufactured andthen assembled. The upper section 30 of cartridge 40 is shown as pieces30′ and 30″. The lengths of the upper section 30 and lower section 10are sufficient to allow removal of section 30 and allow presentation ofan ultra-filtrate in section 10 to an analyzer.

Referring collectively to FIGS. 4A-4M, various pieces of the cartridgeare hidden sequentially in order to reveal underneath the hiddensections of the cartridge, without having to view cross-sections. FIG.4A shows a schematic drawing showing details of a top view of theultra-filtration cartridge 40 used for preparing an ultra-filtrateaccording to the second embodiment of the ultra-filtration cartridge,comprising the upper section 30 shown in two parts 30′ and 30″, and thelower section 10, with section 30″ at the top. FIG. 4B shows a frontview of the cartridge 40 shown in FIG. 4A. FIG. 4C shows a top view ofcartridge 40 shown in FIG. 4A, with parts 30″ and lower section 10hidden. FIG. 4D shows a front view of the cartridge 40 shown in FIG. 4C.FIG. 4E shows a top view of cartridge 40 shown in FIG. 4A, with parts30″, lower section 10 and filtration membrane assembly 60 b hidden. FIG.4F shows a front view of the cartridge 40 shown in FIG. 4E. FIG. 4Gshows a schematic drawing showing details of a top view of anultra-filtration cartridge 40 used for preparing an ultra-filtrateaccording to a second embodiment of the ultra-filtration cartridge,comprising the upper section 30 shown in two parts 30′ and 30″, and thelower section 10, with section 30′ at the top. FIG. 4H shows a frontview of the cartridge 40 shown in FIG. 4G. FIG. 4J shows a top view ofcartridge 40 shown in FIG. 4G, with parts 30′ and lower section 10hidden. FIG. 4K shows a front view of the cartridge 40 shown in FIG. 4J.FIG. 4L shows a top view of cartridge 40 shown in FIG. 4G, with parts30′, lower section 10 and filtration membrane assembly 60 b hidden. FIG.4M shows a front view of the cartridge 40 shown in FIG. 4L. Details ofthe filtration membrane assembly 60 b are shown collectively in FIGS.5B-5J.

Referring collectively to FIGS. 5B-5J, the views of the filtrationmembrane assembly 60 b are described. FIG. 5A shows a schematic drawingshowing details of a front view of the filtration membrane assembly 60 bshown in FIG. 4D and FIG. 4K. FIG. 5B shows a top view of the filtrationmembrane assembly 60 b shown in FIG. 5A. FIG. 5C shows a bottom view ofthe filtration membrane assembly 60 b shown in FIG. 5A. FIG. 5D shows afirst perspective view of the filtration membrane assembly 60 b shown inFIG. 5A. FIG. 5E shows a second perspective view of the filtrationmembrane assembly 60 b shown in FIG. 5A. FIG. 5F shows a thirdperspective view of the filtration membrane assembly 60 b shown in FIG.5A. FIG. 5G shows a fourth perspective view of the filtration membraneassembly 60 b shown in FIG. 5A. FIG. 5H shows a cross-sectional view ofthe filtration membrane assembly 60 b shown in FIG. 5A along line H-H.FIG. 5J shows a detailed view of detail J shown in FIG. 5H showing aschematic representation of the membrane 67 b.

Referring collectively to FIGS. 6A-3J, and FIGS. 7A-7T shown is a thirdembodiment of a disposable ultra-filtration cartridge 50 for automaticpreparation of sample ultra-filtrate. Cartridge 50 is similar tocartridge 20 and accordingly, elements common to both cartridges sharecommon reference numerals, but letter “c” appended at the end ofreference numerals to indicate a different embodiment; the letter “a” isused for cartridge 20 and the letter “b” is used for cartridge 40. Thepipetting tip 70 was previously described when cartridge 20 wasdescribed. A first difference between cartridge 50 and cartridge 20 arethat the filtration membrane assembly 60 c shown in FIGS. 7F and 7M arevery different, and details of the filtration membrane assembly 60 c areshown collectively in FIGS. 8A-8J. The second difference is regardingthe dead-end channel 51 a shown in FIG. 1E, which is depicted as agroove in the body of the cartridge 20. The dead-end channel 51 c incartridge 50 is depicted as a piece of tubing with a closed end 53 c andthe open end 49 c inserted into the filtration chamber outlet 49 c. Asmentioned previously, the open end and the outlet are coincidental,hence the same indicia 49 c. A piece of tubing performs the samefunction as a groove described previously for cartridge 20, and are bothwithin the scope of the invention.

The disposable ultra-filtration cartridge 50 is depicted in three majorpieces: 50′, 50″, and 50′″. FIG. 6A shows a schematic drawing showingdetails of a top view of an assembly comprising an ultra-filtrationcartridge 50 according to a third embodiment of the ultra-filtrationcartridge, engaged with a pipetting tip 70, used for preparing anultra-filtrate. FIG. 6B shows a right side view of the assemblycomprising the cartridge 50 and the pipetting tip 70 shown in FIG. 6A.FIG. 6C shows a first cross-sectional view through the assemblycomprising the cartridge 50 and the pipetting tip 70 shown in FIG. 6Balong line C-C. FIG. 6D shows a perspective view of the cartridge 50shown FIG. 6B and FIG. 6F. FIG. 6E shows a perspective view of thepipetting tip 70 shown FIG. 6B and FIG. 6F. FIG. 6F shows a front viewof the assembly comprising the cartridge 50 and the pipetting tip 70shown in FIG. 6A. FIG. 6G shows a second cross-sectional view throughthe assembly comprising the cartridge 50 and the pipetting tip 70 shownin FIG. 6F along line G-G. FIG. 6H shows a third cross-sectional viewthrough the assembly comprising the cartridge 50 and the pipetting tip70 shown in FIG. 6F along line H-H. FIG. 6J shows an enlarged of thecross-sectional view shown in FIG. 6H.

FIG. 7A shows a schematic drawing showing details of a top view of anultra-filtration cartridge 50 used for preparing an ultra-filtrateaccording to a third embodiment of the ultra-filtration cartridge, shownin three parts 50′, 50″ and 50′″, with the part 50′″ at the bottom. FIG.7B shows a front view of the cartridge 50 shown in FIG. 7A. FIG. 7Cshows a top view of cartridge 50 shown in FIG. 7A, with front part 50′″hidden. FIG. 7D shows a front view of the cartridge 50 shown in FIG. 7C.FIG. 7E shows a top view of cartridge 50 shown in FIG. 7A, with thefront part 50′″ and the middle part 50″ hidden. FIG. 7F shows a frontview of the cartridge 50 shown in FIG. 7E. FIG. 7G shows a top view ofthe cartridge 50 shown in FIG. 7A, with the front part 50′″, the middlepart 50″ and the and filtration membrane assembly 60 c hidden. FIG. 7Hshows a front view of the cartridge 50 shown in FIG. 7G. FIG. 7J shows aschematic drawing showing details of a top view of an ultra-filtrationcartridge 50 used for preparing an ultra-filtrate according to a thirdembodiment of the ultra-filtration cartridge, shown in three parts 50′,50″ and 50′″, with the part 50′ at the bottom. FIG. 7K shows a frontview of the cartridge 50 shown in FIG. 7J. FIG. 7L is a top view ofcartridge 50 shown in FIG. 7J, with back part 50′ hidden. FIG. 7M showsa front view of the cartridge 50 shown in FIG. 7L. FIG. 7N shows a topview of cartridge 50 shown in FIG. 7J, with the back part 50′ and thefiltration membrane assembly 60 c hidden. FIG. 7P shows a front view ofthe cartridge 50 shown in FIG. 7N. FIG. 7R shows a top view of thecartridge 50 shown in FIG. 7A, with the back part 50′, the filtrationmembrane assembly 60 c and the middle part 50″ hidden. FIG. 7S shows afront view of the cartridge 50 shown in FIG. 7R. FIG. 7T is across-sectional view through the cartridge 50 shown in FIG. 7K alongline T-T.

Regarding filtration membrane assembly 60 c, FIG. 8A shows a schematicdrawing showing details of a front view of the filtration membraneassembly 60 c shown in FIG. 6F and FIG. 6M. FIG. 8B shows a top view ofthe filtration membrane assembly 60 c shown in FIG. 8A. FIG. 8C shows abottom view of the filtration membrane assembly 60 c shown in FIG. 8A.FIG. 8D shows a first perspective view of the filtration membraneassembly 60 c shown in FIG. 8A. FIG. 8E shows a second perspective viewof the filtration membrane assembly 60 c shown in FIG. 8A. FIG. 8F showsa third perspective view of the filtration membrane assembly 60 c shownin FIG. 8A. FIG. 8G shows a fourth perspective view of the filtrationmembrane assembly 60 c shown in FIG. 8A. FIG. 8H shows a cross-sectionalview of the filtration membrane assembly 60 c shown in FIG. 8A alongline H-H. FIG. 8J shows a detailed view of detail J shown in FIG. 8Hshowing a schematic representation of the membrane 67 c.

The filtration membrane assemblies 60 a, 60 b, and 60 c for cartridges20, 40, and 50 respectively comprise hollow fiber filtration membranes,wherein the outside represents the retentate side and the inside (lumenof the hollow fibers) represents the filtrate side. A person ofreasonable skill in the art will appreciate that other membraneconfigurations can be used, and two other examples of membraneconfigurations are provided and referenced as 60 d and 60 e.

Filtration membrane assembly 60 d also comprises hollow fiber filtrationmembranes, but the inside represents the retentate side and the outsiderepresents the filtrate side. FIG. 9A shows a schematic drawing showingdetails of a top view of another embodiment 60 d of a filtrationmembrane assembly. FIG. 9B shows a back view of the filtration membraneassembly 60 d shown in FIG. 9A. FIG. 9C shows a front view of thefiltration membrane assembly 60 d shown in FIG. 9A. FIG. 9D shows aright side view of the filtration membrane assembly 60 d shown in FIG.9A. FIG. 9E shows a first perspective view of the filtration membraneassembly 60 d shown in FIG. 9A. FIG. 9F shows a second perspective viewof the filtration membrane assembly 60 d shown in FIG. 9A. FIG. 9G showsa third perspective view of the filtration membrane assembly 60 d shownin FIG. 9A. FIG. 9H shows a fourth perspective view of the filtrationmembrane assembly 60 d shown in FIG. 9A. FIG. 9J shows a cross-sectionalview of the filtration membrane assembly 60 d shown in FIG. 9C alongline J-J. FIG. 9K shows a detailed view of detail K shown in FIG. 9Jshowing a schematic representation of the membrane 67 d.

Filtration membrane assembly 60 e comprises a curved sheet of membrane.FIG. 10A shows a schematic drawing showing details of a top view ofanother embodiment 60 e of a filtration membrane assembly. FIG. 10Bshows a back view of the filtration membrane assembly 60 e shown in FIG.9A. FIG. 100 shows a front view of the filtration membrane assembly 60 eshown in FIG. 10A. FIG. 10D shows a right side view of the filtrationmembrane assembly 60 e shown in FIG. 10A. FIG. 10E shows a firstperspective view of the filtration membrane assembly 60 e shown in FIG.10A. FIG. 10F shows a second perspective view of the filtration membraneassembly 60 e shown in FIG. 10A. FIG. 10G shows a third perspective viewof the filtration membrane assembly 60 e shown in FIG. 10A. FIG. 10Hshows a fourth perspective view of the filtration membrane assembly 60 eshown in FIG. 10A. FIG. 10J shows a first cross-sectional view of thefiltration membrane assembly 60 e shown in FIG. 10B along line J-J. FIG.10K shows a second cross-sectional view of the filtration membraneassembly 60 e shown in FIG. 100 along line K-K. Other embodimentscomprise one or more layers of flat membranes, and fluted membranes.

Referring collectively to FIGS. 11A-11E, shown is an automatedworkstation 100 for automatically preparing sample ultra-filtrates indisposable ultra-filtration cartridges. Although any disposableultra-filtration cartridge similar to the ones described previously canbe used, and therefore labeled 142, the cartridge 142 is very similar tothe third embodiment ultra-filtration cartridge 50, illustratedcollectively in FIGS. 6A-6J and FIGS. 7A-7T. FIG. 11A shows a schematicdrawing showing details of a top view of a workstation 100 forautomatically preparing sample ultra-filtrate from a sample. FIG. 11Bshows a top view of the workstation 100 shown in FIG. 11A. FIG. 11Cshows a detailed view of detail C shown in FIG. 11B showing details ofultra-filtration cartridges in an ultra-filtration cartridge rack, andultra-filtration cartridge reservoir containing sample ultra-filtrate,in an analyzer sector for presenting sample ultra-filtrate to theanalyzer. FIG. 11D shows a first perspective view of the workstation 100shown in FIG. 11A. FIG. 11E shows a second perspective view of theworkstation 100 shown in FIG. 11A.

The embodiment of a workstation 100 shown collectively in FIGS. 11A-11Ehas several features, but the features required in a workstation dependon for example, if the workstation is used as a stand-alone machine, andif the workstation is integrated in an automated laboratory. Moreover,there are features that are not shown that are present in someembodiments. As examples which should not be considered limiting inanyway, some of these features are: a) cartridge rack detectors fordetecting the presence of a cartridge rack on the base at thepredetermined locations; b) cartridge rack detectors output element forsignaling the presence of a cartridge rack to the controller; c) sampletube rack detectors for detecting the presence of a sample tube racks onthe base at the predetermined locations; d) sample tube rack detectorsoutput element for signaling the presence of a sample tube rack to thecontroller; e) pipetting tip rack detectors for detecting the presenceof a pipetting tip racks on the base at the predetermined locations; f)pipetting tip rack detectors output element for signaling the presenceof a pipetting tip rack to the controller; g) rack position detectors;h) pins disposed on the base for enabling the different types of racksto be placed in the correct rack positions; i) sensors mounted slightlybelow the surface of the base in predetermined positions, which can beactivated by providing the racks with magnets strong enough to activatethe sensors; j) optical interrupters where a rack interrupts a lightpath; k) indicia reader for tracking the sample tubes, sample tuberacks, ultra-filtration cartridges, ultra-filtration cartridge racks,ultra-filtration cartridge reservoirs containing sample ultra-filtrate,analyzer sectors for presenting sample ultra-filtrates to an analyzer,pipetting tip racks. Some examples of indicia, which should not beconsidered limiting in any way, include one-dimensional barcodes, atwo-dimensional barcodes, and radio frequency identification tagattached to the sample tubes and the ultra-filtration cartridges. Manyof these features are described in the prior art, for example U.S. Pat.No. 7,141,213.

Still referring collectively to FIGS. 11A-11E, shown in embodiment 100of a workstation are a pipetting tool 110 for releasably holding apipetting tip, a pipetting tool carriage 112 for supporting andcooperating with pipetting tool 110, a pipetting tool carriage movablearm 114 for supporting and moving pipetting tool carriage, a pipettingtip rack 120 for storing pipetting tips 70, a pipetting tool carriagemovable arm carriage 116. On the left side of the workstation 100 isshown a gripping tool 130 for gripping for example, a sample tube or anultra-filtration cartridge, to enable transportation thereof. Also shownare a gripping tool carriage 132 for supporting and cooperating withgripping tool, a gripping tool carriage movable arm 134 for supportingand moving gripping tool carriage, a gripping tool carriage movable arm136, a track for facilitating movement of pipetting tool carriagemovable arm carriage 116 and the gripping tool carriage movable arm 136(shown as 138), an ultra-filtration cartridge rack 140, anultra-filtration cartridge 142, a projected member 144 in theultra-filtration cartridge rack, for enabling proper orientation ofultra-filtration cartridge with respect to X-Z and Y-Z planes, when thecartridge is located in the ultra-filtration rack for processing asample. Also shown are, a sample tube rack 150, sample tube 152, a wastecontainer 160 for receiving ejected used pipetting tip, a controller 170for controlling the workstation, a controller data input element anddisplay touch screen 172, a sample delivery site on the workstation forreceiving samples in sample tubes contained in sample tube racks (204),an ultra-filtration cartridge rack site for on the workstation forhousing ultra-filtration cartridges contained in ultra-filtrationcartridge racks (206), and an analyzer sector site on the workstationfor housing analyzer sectors (208).

Referring collectively to FIGS. 12A-12D, FIG. 12A shows a schematicdrawing showing details of a top view of an ultra-filtration system 800for automatically preparing serum or plasma ultra-filtrate from a sampleand presenting the ultra-filtrate to an analyzer for measuring freetherapeutic drugs and hormones in serum or plasma. FIG. 12B shows a topview of the system 800 shown in FIG. 12A. FIG. 12C shows perspectiveview of the system 800 shown in FIG. 12A. FIG. 12D shows a detailed viewof detail D shown in FIG. 12C showing details of ultra-filtrationcartridges 142 in an ultra-filtration cartridge rack 140,ultra-filtration cartridge reservoir containing sample ultra-filtrate190 in an analyzer sector 180 for presenting sample ultra-filtrate tothe analyzer, and ultra-filtration cartridge reservoir 190 containingsample ultra-filtrate in an analyzer sector 180 on a transport track 400used to present the sample ultra-filtrate to the analyzer 300.

Referring to FIG. 12D and FIG. 110, shown is a projected member 144 inthe ultra-filtration cartridge rack 140, for enabling proper orientationof ultra-filtration cartridge with respect to X-Z and a Y-Z axes, whenthe cartridge is located in the ultra-filtration cartridge rack forprocessing a sample. This feature is not required with the secondembodiment 40 of an ultra-filtration cartridge, which has a singleopening at the top, having a center approximately concentric with thebottom of the cartridge. Therefore there is no concern that thepipetting tip will crash on the cartridge 40. However the concern withrespect to the third embodiment of the cartridge 50, as shown in FIG.12D, is addressed by, for example which should be considered limiting inany way, the projected members 144 between each holding position in therack 140. In embodiments 20 and 50, the openings 27 a and 27 crespectively used by the analyzer probe for accessing sampleultra-filtrate, are approximately concentric with the bottom of therespective cartridge. Therefore when the ultra-filtrate is presented toan analyzer in ultra-filtrate reservoirs in any of the embodimentdescribed, no orientation of the cartridge ultra-filtrate reservoirswith respect to X-Z or Y-Z planes is required.

While the above description provides example embodiments, it will beappreciated that the present invention is susceptible to modificationand change without departing from the fair meaning and scope of theaccompanying claims. Accordingly, what has been described is merelyillustrative of the application of aspects of embodiments of theinvention. Numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein. Furthermore, the discussed combination of features might not beabsolutely necessary for the inventive solution.

REFERENCES CITED

-   1. U.S. Pat. No. 7,816,124-   2. U.S. Pat. No. 7,807,450-   3. U.S. patent application Ser. No. 13/549,443-   4. U.S. Pat. No. 4,474,071-   5. U.S. Pat. No. 7,141,213.

1. An automated workstation for preparing ultra-filtrate in one or more disposable ultra-filtration apparatus, the automated workstation operating in cooperation with a controller and comprising: a base; one or more cartridge racks for holding one or more disposable ultra-filtration cartridges of the one or more disposable ultra-filtration apparatus, and cartridge rack positions on the base for positioning the one or more cartridge racks in predetermined locations; cartridge rack detectors for detecting the presence of a cartridge rack of the one or more cartridge racks on the base at the predetermined locations, the cartridge rack detectors having an output element for signaling the presence of the cartridge rack to the controller; one or more sample tube racks for holding one or more sample tubes, and sample tube rack positions on the base for positioning the one or more sample tube racks in predetermined locations; sample tube rack detectors for detecting the presence of a sample tube rack of the one or more sample tube racks on the base at the predetermined locations, the sample tube rack detectors having an output element for signaling the presence of the sample tube rack to the controller; one or more pipetting tip racks for holding one or more disposable pipetting tips of the one or more disposable ultra-filtration apparatus, and pipetting tip rack positions on the base for positioning the one or more pipetting tip racks in predetermined locations; pipetting tip rack detectors for detecting the presence of a pipetting tip rack of the one or more pipetting tip racks on the base at the predetermined locations, the pipetting tip rack detectors having an output element for signaling the presence of the pipetting tip rack to the controller; a pipetting tool for releasably engaging the one or more disposable pipetting tips; a movable arm, supported from the base, the movable arm supporting the pipetting tool; and a waste container for receiving the one or more disposable pipetting tips released by the pipetting tool; wherein the pipetting tool is configured to apply a force to move a piston of the one or more disposable pipetting tips in a first direction.
 2. The automated workstation according to claim 1, wherein the pipetting tool further includes: resilient fingers that open radially by movement against the force exerted by a spring, for grabbing a pipetting tip piston gripping stem of the one or more disposable pipetting tips; and an outer sleeve surrounding the resilient fingers for frictionally engaging a pipetting tip housing recess that is disposed at a pipetting tip housing gripping end of the one or more disposable pipetting tips; such that a pipetting tip housing piston flange stop of the one or more disposable pipetting tips and a pipetting tip piston flange lower face of the one or more disposable pipetting tips cooperate to enable release of the one or more disposable pipetting tips from the pipetting tool into the waste container.
 3. The automated workstation according to claim 1, wherein the pipetting tool is configured to relax the force applied to the piston of the disposable pipetting tip, and is further configured to accommodate movement of the piston in a second direction, the second direction being opposite to the first direction.
 4. The automated workstation according to claim 1, further comprising an indicia reader for tracking the one or more sample tubes and the one or more disposable ultra-filtration cartridges, wherein the indicia comprises one of a one-dimensional barcode, a two-dimensional barcode, and a radio frequency identification tag attached to the one or more sample tubes and the one or more disposable ultra-filtration cartridges.
 5. The automated workstation according to claim 1, further comprising a delivery site on the base for placement on the base of at least one cartridge rack of the one or more cartridge racks, at least one sample tube rack of the one or more sample tube racks, and at least one pipetting tip rack of the one or more pipetting tip racks.
 6. The automated workstation according to claim 1, wherein the pipetting tool is further configured to: repeatedly move the piston of the one or more disposable pipetting tips in the first direction to pressurize trapped air in the one or more disposable ultra-filtration cartridges; and provide depressurization of the trapped air in the one or more disposable ultra-filtration cartridges between consecutive movements of the piston of the one or more disposable pipetting tips.
 7. The automated workstation according to claim 6, wherein the pipetting tool is further configured to provide the depressurization of the trapped air in a dead-end channel of the one or more disposable ultra-filtration cartridges between consecutive movements of the piston of the one or more disposable pipetting tips by accommodating movement of the piston in a second direction, the second direction being opposite to the first direction.
 8. The automated workstation according to claim 1, wherein each cartridge rack of the one or more cartridge racks supports the one or more disposable ultra-filtration cartridges having a top end and a bottom end in an upright position. 